Comparing Heart Outcomes Among GLP-1 Receptor Agonists for Diabetes Patients

In recent years, a surge of anti-obesity medications has emerged, closely followed by research into their effects and potential side effects. Endocrine News highlights findings from two significant studies focusing on the cardiovascular impacts of glucagon-like peptide-1 receptor agonists (GLP-1RAs) on heart health.

Key Insights Among individuals suffering from type 2 diabetes and atherosclerotic cardiovascular disease (CVD), the dual agonist tirzepatide was found to be noninferior to the selective GLP-1RA dulaglutide for preventing major adverse cardiovascular events, which include cardiovascular-related mortality, myocardial infarction (MI), and stroke. Additionally, preliminary analyses suggest that tirzepatide may be linked to a lower occurrence of non-cardiovascular-related deaths.

Importantly, both semaglutide and liraglutide have been identified as preferable for cardiovascular risk reduction in type 2 diabetes patients at moderate cardiovascular risk levels. The critical takeaway from these findings is that GLP-1RAs are suitable not only for patients with elevated cardiovascular risks but also for those categorized as having moderate risks.

The studies published at the end of 2025 provided empirical data demonstrating that, while GLP-1RAs have significant therapeutic advantages, there are notable differences in efficacy among the available agents in this class. With recent federal policy changes aimed at enhancing access to GLP-1RAs, potentially allowing millions more patients to benefit from these treatments, it's vital to evaluate their safety profiles and effectiveness more closely. The collective findings from these studies improve our comprehension of the distinctive characteristics inherent in GLP-1RAs, potentially enabling more personalized treatment approaches based on individual patient requirements.

Tirzepatide vs. Dulaglutide Stephen J. Nicholls, MB, BS, PhD, from Monash University in Australia, conducted a head-to-head comparison of tirzepatide and dulaglutide in their study entitled "Cardiovascular Outcomes with Tirzepatide versus Dulaglutide in Type 2 Diabetes," published in the New England Journal of Medicine (NEJM) last December. The SURPASS-CVOT trial was designed to answer crucial questions concerning the outcomes associated with combinatorial therapy and improved tolerability of new incretin therapies for a cohort of 6,586 patients with type 2 diabetes who were assigned to the tirzepatide group and 6,579 to the dulaglutide group, followed over four years.

The main endpoint of the study was the timing of the first major cardiovascular adverse event (MACE) involving cardiovascular-related mortality, MI, or stroke. Secondary outcomes assessed included cardiovascular mortality and all-cause mortality, as well as additional composite cardiovascular events (such as coronary revascularizations and heart-failure incidents), renal function changes over three years, and alterations in A1c levels, body weight, blood pressure, and lipid profiles over varying periods.

The findings demonstrated that tirzepatide was as safe and effective as dulaglutide in preventing major cardiovascular incidents, with a similar profile for adverse effects, particularly noting an increase in gastrointestinal issues with tirzepatide. However, tirzepatide exhibited superior benefits in weight loss and A1c reductions. Notably, the composite outcomes involving coronary revascularization and overall mortality were more favorable with tirzepatide, highlighting its clinical significance. Nicholls emphasized the unexpected findings regarding reduced all-cause mortality, particularly from non-cardiovascular sources, suggesting further exploration is warranted to understand underlying mechanisms.

"The question remains how the mechanisms of incretin agonists effectively mitigate cardiovascular events," said Nicholls. He acknowledged the necessity of continued research to identify contributory factors beyond weight loss and glycemic control. Furthermore, he referenced an ongoing trial examining tirzepatide in patients at high cardiovascular risk but without type 2 diabetes, indicating the broader implications of this research.

Comparative Outcomes Among GLP-1RAs: Dulaglutide, Exenatide, Liraglutide, and Semaglutide A separate study published in September in Diabetes Research and Clinical Practice compared the cardiovascular outcomes of four GLP-1RAs—dulaglutide, exenatide, liraglutide, and semaglutide—among adults with type 2 diabetes who presented moderate cardiovascular risk. Dr. Stacey M. Sklepinski, a family medicine resident, and Dr. Rozalina G. McCoy from the University of Maryland highlighted a gap in research regarding the direct comparison of cardiovascular outcomes related to these agents. Their study targeted a population whose predicted risk for adverse events falls between 1-5% within a year.

The researchers noted that clinicians often select medications based on insurance formularies rather than available comparative efficacy data, and hence, understanding the differential effects of these medications is crucial, especially amidst increasing usage and accessibility.

Using a target trial design provides a framework approximating randomized-controlled trial results. Their investigation encompassed 35,572 patients who began treatment with dulaglutide, 4,376 with exenatide, 8,843 with liraglutide, or 33,063 with semaglutide from 2019 to 2021. Results demonstrated that both liraglutide and semaglutide were associated with a significantly lower risk of MACE, expanded MACE, all-cause mortality, acute strokes, and revascularization outcomes compared to dulaglutide.

McCoy emphasized the importance of examining the co-use of GLP-1RAs and sodium-glucose cotransporter-2 inhibitors (SGLT2is), which are also shown to effectively reduce cardiovascular events in type 2 diabetes patients across varied cardiovascular risk levels. However, direct evidence supporting the superiority of combined use remains lacking.

In conclusion, as GLP-1RAs gain prominence in diabetes treatment, nuanced understanding of their cardiovascular impacts and potential for personalized therapy is increasingly vital.